VCV002438511.4 - ClinVar

NM_020442.6(VARS2):c.1346G>A (p.Trp449Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020442.6(VARS2):c.1346G>A (p.Trp449Ter)

Variation ID: 2438511 Accession: VCV002438511.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 30920385 (GRCh38) [ NCBI UCSC ] 6: 30888162 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 5, 2023	Aug 25, 2024	Aug 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020442.6:c.1346G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065175.4:p.Trp449Ter	nonsense
NM_001167733.3:c.926G>A	NP_001161205.1:p.Trp309Ter	nonsense
NM_001167734.2:c.1436G>A	NP_001161206.1:p.Trp479Ter	nonsense
NM_020442.5:c.1346G>A
NC_000006.12:g.30920385G>A
NC_000006.11:g.30888162G>A
NG_034224.1:g.11178G>A

... more HGVS ... less HGVS

Protein change

W309*, W449*, W479*

Other names

Canonical SPDI

NC_000006.12:30920384:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VARS2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	408	505

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Combined oxidative phosphorylation defect type 20	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 24, 2023	RCV003139263.5
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 28, 2022	RCV004697269.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 24, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 20 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004039378.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: Variant summary: VARS2 c.1346G>A (p.Trp449X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: VARS2 c.1346G>A (p.Trp449X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 250068 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the South Asian subpopulation in the gnomAD database. To our knowledge, no occurrence of c.1346G>A in individuals affected with Combined Oxidative Phosphorylation Defect Type 20 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Uncertain significance (Jan 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 20 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003820355.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198978.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024

Comment:

Variant summary: VARS2 c.1346G>A (p.Trp449X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 250068 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the South Asian subpopulation in the gnomAD database. To our knowledge, no occurrence of c.1346G>A in individuals affected with Combined Oxidative Phosphorylation Defect Type 20 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Aug 25, 2024

ClinVar Genomic variation as it relates to human health

NM_020442.6(VARS2):c.1346G>A (p.Trp449Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...